Role of microRNAs in synovial fibroblast biology and functions

microRNA 在滑膜成纤维细胞生物学和功能中的作用

• 批准号: RGPIN-2017-06360
• 负责人: Kapoor, Mohit
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711987
• 关键词: Role; microRNAs; synovial; fibroblast; biology

Background/Rationale: Synovial fibroblasts are predominant cells present in the synovial membrane and are crucial for the maintenance of joint homeostasis by contributing towards the production of extracellular matrix (ECM). Synovial fibroblasts in response to specific stimuli (cytokines and growth factors) acquire myofibroblast-type phenotype and produce excessive amount of ECM resulting in tissue fibrosis and loss of function. The endogenous mediators that control synovial fibroblast functions (differentiation, migration, proliferation and adhesion) and ECM production are largely unknown. MicroRNAs (miRNAs) are small non-coding RNAs that regulate more than 60% of all coding genes and play pivotal roles in various pathophysiological processes. The exact role of microRNAs in synovial fibroblast biology and functions is largely unknown. Preliminary Studies: Our recent studied have identified a panel of microRNAs (miR-23a-3p, 24-3p, 27a-3p, 27b-3p, 29c-3p, 186-5p and 378a-5p) that are highly abundant in normal human synovium, especially synovial fibroblasts and their expression is dramatically elevated in response to inflammatory stimuli, IL-1. The specific roles of these identified miRNAs in synovial biology and its functions has never been reported. Our preliminary data shows that, in response to inflammatory IL-1 stimulation (and not TNF- or IL-6), all these miRNAs show significant elevation in their expression. Our pilot data on miR-27b-3p strongly suggest that miR-27b-3p is activated by IL-1 and is involved in fibroblast-myofibroblast differentiation and ECM production. We anticipate that other identified miRNAs may also play a role in certain synovial fibroblast functions associated with ECM production. Hypothesis: miRNAs may play a central role in controlling the ECM production by inducing the differentiation of synovial fibroblast to myofibroblast-like cells as well as in synovial fibroblast migration, proliferation and adhesive signaling in the synovium. To examine the exact role(s) of miRNAs in ECM production, the major objectives of this program are: 1. Determine the role of identified microRNAs in synovial fibroblast differentiation (fibroblast-myofibroblast like cells), proliferation and survival. 2. Determine the role of identified microRNAs in synovial fibroblast migration, adhesive signaling, ECM contraction and its production. 3. Identify the signaling pathways through which these miRNAs operate in synovial fibroblasts to mediate ECM production. Significance: This research program will enable significant advancement in the field of synovial fibroblast biology and help identify crucial endogenous mechanisms that control synovial fibroblast-myofibroblast differentiation, migration, adhesion and ECM production. This program will also provide world-class training to create highly skilled and qualified research personnel.

背景/依据：滑膜成纤维细胞是存在于滑膜中的主要细胞，并且通过促进细胞外基质（ECM）的产生而对维持关节稳态至关重要。滑膜成纤维细胞响应于特定刺激（细胞因子和生长因子）获得肌成纤维细胞型表型并产生过量的ECM，导致组织纤维化和功能丧失。控制滑膜成纤维细胞功能（分化、迁移、增殖和粘附）和ECM产生的内源性介质在很大程度上尚不清楚。microRNAs（miRNAs）是一类小分子非编码RNA，调控着60%以上的编码基因，在多种病理生理过程中发挥着重要作用。microRNA在滑膜成纤维细胞生物学和功能中的确切作用在很大程度上是未知的。 初步研究：我们最近的研究已经鉴定了一组microRNA（miR-23 a-3 p、24- 3 p、27 a-3 p、27 b-3 p、29 c-3 p、186- 5 p和378 a-5 p），它们在正常人滑膜中，特别是滑膜成纤维细胞中高度丰富，并且它们的表达响应于炎症刺激IL-1而显著升高。这些鉴定的miRNAs在滑膜生物学中的具体作用及其功能尚未报道。我们的初步数据显示，在炎症性IL-1刺激（而不是TNF-或IL-6）的反应中，所有这些miRNAs的表达都显着升高。我们关于miR-27 b-3 p的初步数据强烈表明，miR-27 b-3 p被IL-1激活，并参与成纤维细胞-肌成纤维细胞分化和ECM产生。我们预期其他鉴定的miRNAs也可能在与ECM产生相关的某些滑膜成纤维细胞功能中发挥作用。 假设：miRNAs通过诱导滑膜成纤维细胞分化为肌成纤维细胞样细胞，在滑膜成纤维细胞迁移、增殖和粘附信号传导中发挥重要作用。 为了研究miRNA在ECM产生中的确切作用，该计划的主要目标是： 1.确定鉴定的microRNA在滑膜成纤维细胞分化（成纤维细胞-肌成纤维细胞样细胞）、增殖和存活中的作用。 2.确定鉴定的microRNA在滑膜成纤维细胞迁移、粘附信号传导、ECM收缩及其产生中的作用。 3.确定这些miRNA在滑膜成纤维细胞中介导ECM产生的信号通路。 重要性：这项研究计划将使滑膜成纤维细胞生物学领域取得重大进展，并有助于确定控制滑膜成纤维细胞-肌成纤维细胞分化、迁移、粘附和ECM产生的关键内源性机制。 该计划还将提供世界一流的培训，以培养高技能和合格的研究人员。